Substituted aryl and cycloalkyl imidazolones; a new class of GABA brain receptor ligands

ABSTRACT

Disclosed are compounds of the formula: ##STR1## wherein: T is NH, O, or S; 
     X is hydrogen, hydroxyl, lower alkyl, or an optionally substituted amide; 
     the W ring is an optionally substituted aryl or heteroaryl group; and ##STR2## represents an optionally substituted benzo group or an optionally substituted 5, 6, 7, or 8 membered ring. 
     These compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory.

This is a continuation application of Ser. No. 08/461,641 filed Jun. 5,1995, now U.S. Pat. No. 5,637,724.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel imidazolone derivatives whichselectively bind to GABAa receptors. More specifically it relates tosubstituted aryl and cycloalkyl imidazolones and to pharmaceuticalcompositions comprising such compounds. It further relates to the use ofsuch compounds in treating anxiety, sleep and seizure disorders, andoverdoses of benzodiazepine-type drugs, and enhancing alertness.

2. Description of the Related Art

γ-Aminobutyric acid (GABA) is regarded as one of the major inhibitoryamino acid transmitters in the mammalian brain. Over 40 years haveelapsed since its presence in the brain was demonstrated (Roberts &Frankel, J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187:65-69, 1950). Since that time, an enormous amount of effort has beendevoted to implicating GABA in the etiology of seizure disorders, sleep,anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8:21-44, 1985). Widely, although unequally, distributed through themammalian brain, GABA is said to be a transmitter at approximately 30%of the synapses in the brain. In most regions of the brain, GABA isassociated with local inhibitory neurons and only in two regions is GABAassociated with longer projections. GABA mediates many of its actionsthrough a complex of proteins localized both on cell bodies and nerveendings; these are called GABAa receptors. Postsynaptic responses toGABA are mediated through alterations in chloride conductance thatgenerally, although not invariably, lead to hyperpolarization of thecell. Recent investigations have indicated that the complex of proteinsassociated with postsynaptic GABA responses is a major site of actionfor a number of structurally unrelated compounds capable of modifyingpostsynaptic responses to GABA. Depending on the mode of interaction,these compounds are capable of producing a spectrum of activities(either sedative, anxiolytic, and anticonvulsant, or wakefulness,seizures, and anxiety).

1,4-Benzodiazepines continue to be among the most widely used drugs inthe world. Principal among the benzodiazepines marketed arechlordiazepoxide, diazepam, flurazepam, and triazolam. These compoundsare widely used as anxiolytics, sedative-hypnotics, muscle relaxants,and anticonvulsants. A number of these compounds are extremely potentdrugs; such potency indicates a site of action with a high affinity andspecificity for individual receptors. Early electrophysiological studiesindicated that a major action of benzodiazepines was enhancement ofGABAergic inhibition. The benzodiazepines were capable of enhancingpresynaptic inhibition of a monosynaptic ventral root reflex, aGABA-mediated event (Schmidt et al., 1967, Arch. Exp. Path. Pharmakol.258: 69-82). All subsequent electrophysiological studies (reviewed inTallman et al. 1980, Science 207: 274-81, Haefley et al., 1981, Handb.Exptl. Pharmacol. 33: 95-102) have generally confirmed this finding, andby the mid-1970s, there was a general consensus amongelectrophysiologists that the benzodiazepines could enhance the actionsof GABA.

With the discovery of the "receptor" for the benzodiazepines and thesubsequent definition of the nature of the interaction between GABA andthe benzodiazepines, it appears that the behaviorally importantinteractions of the benzodiazepines with different neurotransmittersystems are due in a large part to the enhanced ability of GABA itselfto modify these systems. Each modified system, in turn, may beassociated with the expression of a behavior.

Studies on the mechanistic nature of these interactions depended on thedemonstration of a high-affinity benzodiazepine binding site (receptor).Such a receptor is present in the CNS of all vertebratesphylogenetically newer than the boney fishes (Squires & Braestrup 1977,Nature 166: 732-34, Mohler & Okada, 1977, Science 198: 854-51, Mohler &Okada. 1977, Br. J. Psychiatry 133: 261-68). By using tritiateddiazepam, and a variety of other compounds, it has been demonstratedthat these benzodiazepine binding sites fulfill many of the criteria ofpharmacological receptors; binding to these sites in vitro is rapid,reversible, stereospecific, and saturable. More importantly, highlysignificant correlations have been shown between the ability ofbenzodiazepines to displace diazepam from its binding site and activityin a number of animal behavioral tests predictive of benzodiazepinepotency (Braestrup & Squires 1978, Br. J. Psychiatry 133: 249-60, Mohler& Okada, 1977, Science 198: 854-51, Mohler & Okada, 1977, Br. J.Psychiatry 133: 261-68). The average therapeutic doses of these drugs inman also correlate with receptor potency (Tallman et al. 1980, Science207: 274-281).

In 1978, it became clear that GABA and related analogs could interact atthe low affinity (1 mM) GABA binding site to enhance the binding ofbenzodiazepines to the clonazepam-sensitive site (Tallman et al. 1978,Nature, 274: 383-85). This enhancement was caused by an increase in theaffinity of the benzodiazepine binding site due to occupancy of the GABAsite. This data was interpreted to mean that both GABA andbenzodiazepine sites were allosterically linked in the membrane as partof a complex of proteins. For a number of GABA analogs, the ability toenhance diazepam binding by 50% of maximum and the ability to inhibitthe binding of GABA to brain membranes by 50% could be directlycorrelated. Enhancement of benzodiazepine binding by GABA agonists isblocked by the GABA receptor antagonist (+) bicuculline; thestereoisomer (-) bicuculline is much less active (Tallman et al., 1978,Nature, 274: 383-85).

Soon after the discovery of high affinity binding sites for thebenzodiazepines, it was discovered that a triazolopyridazine couldinteract with benzodiazepine receptors in a number of regions of thebrain in a manner consistent with receptor heterogeneity or negativecooperativity. In these studies, Hill coefficients significantly lessthan one were observed in a number of brain regions, including cortex,hippocampus, and striatum. In cerebellum, triazolopyridazine interactedwith benzodiazepine sites with a Hill coefficient of 1 (Squires et al.,1979, Pharma. Biochem. Behav. 10: 825-30, Klepner et al. 1979,Pharmacol. Biochem. Behav. 11: 457-62). Thus, multiple benzodiazepinereceptors were predicted in the cortex, hippocampus, striatum, but notin the cerebellum.

Based on these studies, extensive receptor autoradiographic localizationstudies were carried out at a light microscopic level. Although receptorheterogeneity has been demonstrated (Young & Kuhar 1980, J. Pharmacol.Exp. Ther. 212: 337-46, Young et al., 1981 J. Pharmacol Exp. ther 216:425-430, Niehoff et al. 1982, J. Pharmacol. Exp. Ther. 221: 670-75), nosimple correlation between localization of receptor subtypes and thebehaviors associated with the region has emerged from the early studies.In addition, in the cerebellum, where one receptor was predicted frombinding studies, autoradiography revealed heterogeneity of receptors(Niehoff et al., 1982, J. Pharmacol. Exp. Ther. 221: 670-75).

A physical basis for the differences in drug specificity for the twoapparent subtypes of benzodiazepine sites has been demonstrated bySieghart & Karobath, 1980, Nature 286: 285-87. Using gel electrophoresisin the presence of sodium dodecyl sulfate, the presence of severalmolecular weight receptors for the benzodiazepines has been reported.The receptors were identified by the covalent incorporation ofradioactive flunitrazepam, a benzodiazepine which can covalently labelall receptor types. The major labeled bands have molecular weights of50,000 to 53,000, 55,000, and 57,000 and the triazolopyridazines inhibitlabeling of the slightly higher molecular weight forms (53,000, 55,000,57,000) (Seighart et al. 1983, Eur. J. Pharmacol. 88: 291-99).

At that time, the possibility was raised that the multiple forms of thereceptor represent "isoreceptors" or multiple allelic forms of thereceptor (Tallman & Gallager 1985, Ann. Rev. Neurosci. 8, 21-44).Although common for enzymes, genetically distinct forms of receptorshave not generally been described. As we begin to study receptors usingspecific radioactive probes and electrophoretic techniques, it is almostcertain that isoreceptors will emerge as important in investigations ofthe etiology of psychiatric disorders in people.

The GABAa receptor subunits have been cloned from bovine and human cDNAlibraries (Schoenfield et al., 1988; Duman et al., 1989). A number ofdistinct cDNAs were identified as subunits of the GABAa receptor complexby cloning and expression. These are categorized into α, β, γ, δ, ε, andprovide a molecular basis for the GABAa receptor heterogeneity anddistinctive regional pharmacology (Shivvers et al., 1980; Levitan etal., 1989). The γ subunit appears to enable drugs like benzodiazepinesto modify the GABA responses (Pritchett et al., 1989). The presence oflow Hill coefficients in the binding of ligands to the GABAa receptorindicates unique profiles of subtype specific pharmacological action.

Drugs that interact at the GABAa receptor can possess a spectrum ofpharmacological activities depending on their abilities to modify theactions of GABA. For example, the beta-carbolines were first isolatedbased upon their ability to inhibit competitively the binding ofdiazepam to its binding site (Nielsen et al., 1979, Life Sci. 25:679-86). The receptor binding assay is not totally predictive about thebiological activity of such compounds; agonists, partial agonists,inverse agonists, and antagonists can inhibit binding. When thebeta-carboline structure was determined, it was possible to synthesize anumber of analogs and test these compounds behaviorally. It wasimmediately realized that the beta-carbolines could antagonize theactions of diazepam behaviorally (Tenen & Hirsch, 1980, Nature 288:609-10). In addition to this antagonism, beta-carbolines possessintrinsic activity of their own opposite to that of the benzodiazepines;they become known as inverse agonists.

In addition, a number of other specific antagonists of thebenzodiazepine receptor were developed based on their ability to inhibitthe binding of benzodiazepines. The best studied of these compounds isan imidazodiazepine (Hunkeler et al., 1981, Nature 290: 514-516). Thiscompound is a high affinity competitive inhibitor of benzodiazepine andbeta-carboline binding and is capable of blocking the pharmacologicalactions of both these classes of compounds. By itself, it possesseslittle intrinsic pharmacological activity in animals and humans(Hunkeler et al., 1981, Nature 290: 514-16; Darragh et al., 1983. Eur.J. Clin. Pharmacol. 14: 569-70). When a radiolabeled form of thiscompound was studied (Mohler & Richards, 1981, Nature 294: 763-65), itwas demonstrated that this compound would interact with the same numberof sites as the benzodiazepines and beta-carbolines, and that theinteractions of these compounds were purely competitive. This compoundis the ligand of choice for binding to GABAa receptors because it doesnot possess receptor subtype specificity and measures each state of thereceptor.

The study of the interactions of a wide variety of compounds similar tothe above has led to the categorizing of these compounds. Presently,those compounds possessing activity similar to the benzodiazepines arecalled agonists. Compounds possessing activity opposite tobenzodiazepines are called inverse agonists, and the compounds blockingboth types of activity have been termed antagonists. This categorizationhas been developed to emphasize the fact that a wide variety ofcompounds can produce a spectrum of pharmacological effects, to indicatethat compounds can interact at the same receptor to produce oppositeeffects, and to indicate that beta-carbolines and antagonists withintrinsic anxiogenic effects are not synonymous.

A biochemical test for the pharmacological and behavioral properties ofcompounds that interact with the benzodiazepine receptor continues toemphasize the interaction with the GABAergic system. In contrast to thebenzodiazepines, which show an increase in their affinity due to GABA(Tallman et al., 1978, Nature 274: 383-85, Tallman et al., 1980, Science207: 274-81), compounds with antagonist properties show little GABAshift (i.e., change in receptor affinity due to GABA) (Mohler & Richards1981, Nature 294: 763-65), and the inverse agonists actually show adecrease in affinity due to GABA (Braestrup & Nielson 1981, Nature 294:472-474). Thus, the GABA shift predicts generally the expectedbehavioral properties of the compounds.

Various compounds have been prepared as benzodiazepine agonists andantagonists. "For Example, U.S. Pat. Nos. 3,455,943, 4,435,403,4,596,808, 4,623,649, and 4,719,210, German Patent No. DE 3,246,932, andLiebigs Ann. Chem. 1986, 1749 teach assorted benzodiazepine agonists andantagonists and related anti-depressant and central nervous systemactive compounds. U.S. Pat. No. 3,455,943 discloses compounds of theformula: ##STR3## wherein R₁ is a member of the group consisting ofhydrogen and lower alkoxy; R₂ is a member of the group consisting ofhydrogen and lower alkoxy; R₃ is a member of the group consisting ofhydrogen and lower alkyl; and X is a divalent radical selected from thegroup consisting of ##STR4## and the non-toxic acid addition saltsthereof.

U.S. Pat. No. 4,435,403 teaches compounds of the formula: ##STR5##wherein R^(C) is hydrogen, lower alkyl, alkoxyalkyl of up to 6 C-atoms,cycloalkyl of 3-6 C-atoms, arylalkyl of up to 8 C-atoms, or (CH₂)_(n)OR₂ wherein R₂₀ is alkyl of up to 6 C-atoms, cycloalkyl of 3-6 C-atomsor arylalkyl of up to 8 C-atoms and n is an integer of 1 to 3; Y isoxygen, two hydrogen atoms or NOR₁, wherein R₁ is hydrogen, lower alkyl,aryl or arylalkyl of up to 6 C-atoms, COR₂, wherein R₂ is lower alkyl ofup to 6 C-atoms, or Y is CHCOOR₃, wherein R₃ is hydrogen or lower alkylor Y is NNR₄ R₅, wherein R₄ and R₅ can be the same or different and eachis hydrogen, lower alkyl, C₆₋₁₀ -aryl, C₇₋₁₀ -arylalkyl or CONR₆ R₇,wherein R₆ and R₇ can be the same or different and each is hydrogen orlower alkyl or R₄ and R₅ together with the connecting N-atom, form a 5-or 6-membered heterocyclic ring which optionally may also contain anO-atom or up to 3 N-atoms and which optionally may be substituted by alower alkyl group; Z is hydrogen, or alkoxy or aralkoxy each of up to 10C-atoms and each optionally substituted by hydroxy, or Z is alkyl of upto 6 C-atoms, C₆₋₁₀ -aryl or C7-10-arylalkyl each of which mayoptionally be substituted by a COOR₈ or a CONR₉ R₁₀ group, wherein R₈ isalkyl of up to 6 C-atoms, and R₉ and R₁₀ can be the same or differentand each is hydrogen or alkyl of up to 6 C-atoms; or Z is NR₉ R₁₀,wherein R₉ and R₁₀ are as defined above; or Z is NR₁₁ CHR₁₂ R₁₃, whereinR₁₁ and R₁₂ each is hydrogen or together form a N═C double bond, whereinR₁₃ is C₁₋₁₀ -alkyl or NR₁₄ R₁₅, wherein R₁₄ and R₁₅ are the same ordifferent and each is hydrogen, OH or alkyl or alkoxy each of up to 6C-atoms, or wherein R₁₂ and R₁₃ together are oxygen, in which case, R₁₁is hydrogen; or Z is COOR₂ wherein R₂ is as defined above; or Y and Z,together with the connecting C-atom, may form a 5- or 6-memberedheterocyclic ring which contains an O-atom, adjoining O- and N-atoms orup to 4 N atoms and which optionally may be substituted by a lower alkylgroup, hydroxy or oxo.

U.S. Pat. No. 4,596,808 discloses compounds of the formula: ##STR6##wherein R^(A) is H, F, Cl, Br, I, NO₂, CN, CH₃, CF₃, SCH₃, NR₁₆ R₁₇ orNHCOR₁₆, wherein R₁₆ of R₁₇ are the same or different and each ishydrogen or alkyl, alkenyl or alkynyl each of up to 6 C-atoms, arylalkylor cycloalkyl each of up to 10 C-atoms, or wherein R₁₆ and R₁₇ togetherform a saturated or unsaturated 3-7 membered heterocyclic ring.

U.S. Pat. No. 4,623,649 teaches compounds of the formula: ##STR7##wherein R₃ is an oxadiazolyl residue of the formula ##STR8## wherein R₅stands for lower alkyl of up to 3 carbon atoms or an ester --CO₂ R₆ withR₆ being hydrogen or lower alkyl of up to 3 carbon atoms, R₄ ishydrogen, lower alkyl of up to 3 carbon atoms, or CH₂ OR₉ wherein R₉ islower alkyl of up to 3 carbon atoms, R^(A) is phenyl or a hydrocarbonresidue containing 2-10 carbon atoms which can be cyclic or acyclic,saturated or unsaturated, branched or unbranched, and which canoptionally be substituted by oxo, formyl OH, O-alkyl of up to 3 carbonatoms or phenyl, and wherein in a cyclic hydrocarbon residue, a CH₂-group can be replaced by oxygen.

U.S. Pat. No. 4,719,210 discloses compounds of the formula: ##STR9##wherein R₁ is hydrogen or a protecting group. R₂ is --CH═CR₄ or --C═CR₄,R₄ is hydrogen or halogen, R₃ is hydrogen, lower alkyl or loweralkoxyalkyl, R^(A) is, inter alia, hydrogen, OR₇, lower alkyl, whichoptionally is substituted with aryl, lower alkoxy or NR₅ R₆, R₅ and R₆can be the same or different and in each case is hydrogen, lower alkylor together with the nitrogen atom a 5-6 member ring, which can containanother heteroatom. R₇ is lower alkyl optionally substituted aryl orarylalkyl, and each compound can contain one or more R^(A) radicalswhich are not hydrogen.

These compounds differ from the compounds of the present invention.These U.S. Patents teach carbocyclic compounds having pyridine orpiperidine rings but lack the imidazolone ring present in the compoundsof the present invention.

German Patent No. DE 3,246,932 discloses compounds of the formula:##STR10## wherein R=halogen, NO₂, CO₂ H, modified CO₂ H, R₂ O, R₂S(O)_(n) ; n=0-2; and R₁ =H, alkyl, cycloalkyl, arylalkyl, aryl, CO₂ H,amino R₂ O, R₂ S(O)_(n). However no examples were exemplified in thispatent with R₁ =aryl.

Liebigs Ann. Chem. 1986, 1749-1764 teaches compounds of the formula:##STR11## where R^(X) is hydrogen, methyl, benzyloxy, or methoxy, and R₃is carboethoxy.

Japanese Patent No JP 57149277 describes a compound of the formula:##STR12##

Meanwell et al, J. Org. Chem.: 60, 1565-1582 (1995) discloses compoundsof the following formula ##STR13##

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact witha GABAa binding site, the benzodiazepine receptor.

The invention provides pharmaceutical compositions comprising compoundsof Formula I. The invention also provides compounds useful in thediagnosis and treatment of anxiety, sleep, and seizure disorders,overdose with benzodiazepine drugs and for enhancement of memory.Accordingly, a broad embodiment of the invention is directed tocompounds of Formula I: ##STR14## wherein: T is NH, O, or S;

X is hydrogen, hydroxyl, lower alkyl, or CONR₁ R₂ where R₁ and R₂independently represent hydrogen or lower alkyl; ##STR15## representsbenzo, thieno, or pyrido, each of which is optionally mono ordisubstituted with halogen, hydroxyl, lower alkyl, amino, mono- ordialkylamino where each alkyl is lower alkyl, or lower alkoxy; and##STR16## wherein: n is 0, 1, 2, or 3;

R₃, R₄, R₅ and R₆ are the same or different and represent hydrogen,halogen, lower alkyl, lower alkoxy, phenyl, or 2-, 3-, or 4-pyridyl; orphenylalkyl or 2-, 3-, or 4-pyridylalkyl where each alkyl is loweralkyl, each of which is mono or disubstituted with halogen, hydroxyl,lower alkyl or alkoxy lower alkyl; and

R₇, R₈, R₉, R₁₀ independently represents hydrogen, lower alkyl; or

R₇ and R₈ together may represent a group of the formula ##STR17## wheren1 is 0, 1, 2.

These compounds are highly selective agonists, antagonists or inverseagonists for GABAa brain receptors or prodrugs of agonists, antagonistsor inverse agonists for GABAa brain receptors. These compounds areuseful in the diagnosis and treatment of anxiety, sleep and seizuredisorders, overdose with benzodiazepine drugs and for enhancement ofmemory.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed by the instant invention can bedescribed by the following general formula I: ##STR18## wherein: T isNH, O, or S;

X is hydrogen, hydroxyl, lower alkyl, or CONR₁ R₂ where R₁ and R₂independently represent hydrogen or lower alkyl; ##STR19## representsbenzo, thieno, or pyrido, each of which is optionally mono ordisubstituted with halogen, hydroxyl, lower alkyl, amino, mono- ordialkylamino where each alkyl is lower alkyl, or lower alkoxy; ##STR20##wherein: n is 0, 1, 2, or 3;

R₃, R₄, R₅ and R₆ are the same or different and represent hydrogen,halogen, lower alkyl, lower alkoxy, phenyl, or 2-, 3-, or 4-pyridyl; orphenylalkyl or 2-, 3-, or 4-pyridylalkyl where each alkyl is loweralkyl, each of which is mono or disubstituted with halogen, hydroxyl,lower alkyl or alkoxy lower alkyl;

R₇, R₈, R₉, R₁₀ independently represents hydrogen, lower alkyl; or

R₇ and R₈ together may represent a group of the formula ##STR21## wheren1 is 0, 1, 2.

In addition, the present invention encompasses compounds of the FormulaII. ##STR22## (the "W ring") represents benzo, thieno, or pyrido, eachof which is optionally mono or disubstituted with halogen, hydroxyl,lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where eachalkyl is lower alkyl; and

R is hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy.

Preferred compounds of Formula II are those where the W ring is benzo orpyrido, each of which is mono or disubstituted with halogen, hydroxyl,lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where eachalkyl is lower alkyl. More preferred compounds of Formula II are thosewhere R is hydrogen or halogen; and the W ring is benzo or pyrido, eachof which is mono or disubstituted with halogen, hydroxyl, lower alkyl,lower alkoxy, amino, or mono- or dialkylamino where each alkyl is loweralkyl.

In addition, the present invention encompasses compounds of the FormulaIII. ##STR23## (the "Y ring") represents benzo or pyrido, each of whichis optionally mono or disubstituted with halogen, hydroxyl, lower alkyl,lower alkoxy, amino, or mono- or dialkylamino where each alkyl is loweralkyl; and

R is hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy.

Preferred compounds of Formula III are those where the Y ring is benzoor pyrido, each of which is mono or disubstituted with halogen,hydroxyl, lower alkyl, lower alkoxy, amino, or mono- or dialkylaminowhere each alkyl is lower alkyl. More preferred compounds of Formula IIIare those where R is hydrogen or halogen; and the Y ring is benzo orpyrido each of which is mono or disubstituted with halogen, hydroxyl,lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where eachalkyl is lower alkyl.

In addition, the present invention encompasses compounds of the FormulaIV. ##STR24## represents benzo or pyrido, each of which is optionallymono or disubstituted with halogen, hydroxyl, lower alkyl, lower alkoxy,amino, or mono- or dialkylamino where each alkyl is lower alkyl.

Preferred compounds of Formula IV are those where the Y ring is benzo orpyrido, each of which is mono or disubstituted with halogen, hydroxyl,lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where eachalkyl is lower alkyl. More preferred compounds of Formula IV are thosewhere the Y ring is benzo or pyrido, each of which is mono ordisubstituted with halogen, hydroxyl, lower alkyl, lower alkoxy, amino,or mono- or dialkylamino where each alkyl is lower alkyl.

In addition, the present invention encompasses compounds of the FormulaV ##STR25## represents benzo or pyrido, each of which is optionally monoor disubstituted with halogen, hydroxyl, lower alkyl, lower alkoxy,amino, or mono- or dialkylamino where each alkyl is lower alkyl.

Preferred compounds of Formula V are those where the Y ring is benzo orpyrido, each of which is mono or disubstituted with halogen, hydroxyl,lower alkyl, lower alkoxy, amino, or mono- or dialkylamino where eachalkyl is lower alkyl. More preferred compounds of Formula V are thosewhere the Y ring is benzo or pyrido, each of which is mono ordisubstituted with halogen, hydroxyl, lower alkyl, lower alkoxy, amino,or mono- or dialkylamino where each alkyl is lower alkyl.

The system used herein for numbering the imidazo portion of thecompounds of Formulae III-V is as follows: ##STR26##

The system used herein for numbering the oxazyl portion of the compoundsof Formulae III-V is as follows: ##STR27##

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds shown belowin Table 1 and their pharmaceutically acceptable salts. Non-toxicpharmaceutically acceptable salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluene sulfonic, hydroiodic, acetic and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which can be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

By benzo as used herein is meant a group of the formula ##STR28##optionally substituted with up to two groups selected from halogen,hydroxyl, lower alkyl, amino, mono- or dialkylamino where each alkyl islower alkyl, or lower alkoxy.

By thieno as used herein is meant a group of the formula ##STR29##optionally substituted with up to two groups selected from halogen,hydroxyl, lower alkyl, amino, mono- or dialkylamino where each alkyl islower alkyl, or lower alkoxy.

By pyrido as used herein is meant a group of the formula ##STR30##optionally substituted with up to two groups selected from halogen,hydroxyl, lower alkyl, amino, mono- or dialkylamino where each alkyl islower alkyl, or lower alkoxy.

By lower alkyl in the present invention is meant straight or branchedchain alkyl groups having 1-6 carbon atoms, such as, for example,methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl.

By lower alkoxy in the present invention is meant straight or branchedchain alkoxy groups having 1-6 carbon atoms, such as, for example,methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy,pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy,and 3-methylpentoxy.

By halogen in the present invention is meant fluorine, bromine,chlorine, and iodine.

By N-alkylpiperazyl in the invention is meant radicals of the formula:##STR31## where R_(a) is lower alkyl as defined above.

Representative imidazolone derivatives according to the invention areshown in Table 1 below. ##STR32##

The number below each compound is its compound number.

The pharmaceutical utility of compounds of this invention are indicatedby the following assay for GABAa receptor activity.

Assays are carried out as described in Thomas and Tallman (J. Bio. Chem.156: 9838-9842, J. Neurosci. 3: 433-440, 1983). Rat cortical tissue isdissected and homogenized in 25 volumes (w/v) of 0.05M Tris HCl buffer(pH 7.4 at 4° C.). The tissue homogenate is centrifuged in the cold (4°)at 20,000×g for 20'. The supernatant is decanted and the pellet isrehomogenized in the same volume of buffer and again centrifuged at20,000×g. The supernatant is decanted and the pellet is frozen at -20°C. overnight. The pellet is then thawed and rehomogenized in 25 volume(original wt/vol) of buffer and the procedure is carried out twice. Thepellet is finally resuspended in 50 volumes (w/vol of 0.05M Tris HClbuffer (pH 7.4 at 40° C.).

Incubations contain 100 ml of tissue homogenate, 100 ml of radioligand0.5 nM (³ H-RO15-1788 ³ H-Flumazenil! specific activity 80 Ci/mmol),drug or blocker and buffer to a total volume of 500 ml. Incubations arecarried for 30 min at 4° C. then are rapidly filtered through GFBfilters to separate free and bound ligand. Filters are washed twice withfresh 0.05M Tris HCl buffer (pH 7.4 at 4° C.) and counted in a liquidscintillation counter. 1.0 mM diazepam is added to some tubes todetermine nonspecific binding. Data are collected in triplicatedeterminations, averaged and % inhibition of total specific binding iscalculated. Total Specific Binding=Total-Nonspecific. In some cases, theamounts of unlabeled drugs is varied and total displacement curves ofbinding are carried out. Data are converted to a form for thecalculation of IC₅₀ and Hill Coefficient (nH). Data for compounds ofthis invention are listed in Table 2.

                  TABLE 2                                                         ______________________________________                                        Compound Number.sup.1                                                                          Ki(nm)                                                       ______________________________________                                        1                3.0                                                          2                4.6                                                          3                14                                                           4                25                                                           5                21                                                           6                81                                                           ______________________________________                                         .sup.1 Compound numbers relate to compounds shown in Table 1.            

The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono-or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Representative methods for the preparation of compounds of the presentinvention are shown in Schemes I-IV. ##STR33##

A procedure for the preparation of the tetrahydrobenzimidazolone isdescribed by Zav'yalov et al. in Chem Heterocycl. Compd.(Engl. Transl.),26: 708 (1990). ##STR34##

As it is used in the above schemes, CDI means carbonyl di-imidazole.

The invention is further illustrated by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures and compounds described therein.

EXAMPLE 1 ##STR35##

A mixture of 2-bromocyclohexanone (6.23 g, 0.035 mol) and urea (2.1 g,0.035 mol) is refluxed in a solution of ammonium acetate (10 g), aceticacid (15 mL) and water (50 mL) for 4 h. Upon cooling slowly to roomtemp, white crystals form in the reaction vessel. The solid is collectedby suction filtration, washed thoroughly with water and ether, and driedin vacuo to afford 4,5,6,7-tetrahydro-2-benzimidazolone (Compound 7).

EXAMPLE 2 ##STR36##

To a suspension of 4,5,6,7-tetrahydro-2-benzimidazolone (0.358 g, 2.595mmol) in dry THF is added Lithium diisopropyl amide (1.5M solution incyclohexane) dropwise at room temperature. The resulting homogeneoussolution is stirred for 10 minutes at room temperature and then2-chloro-7-fluoro-benzoxazole (0.445 g, 2.595 mmol) in THF is added at amoderate rate via syringe. After stirring at room temperature for 1 h,water is added to the reaction vessel and the THF is removed underreduced pressure. The resulting solid is collected via suctionfiltration and washed successively with water, methanol and ether toafford3-(2-(7-fluorobenzoxazyl)-4,5,6,7-tetrahydrobenzimidazol-2-(1H)-one;(Compound 8); mp 250°-253° C. as a pale yellow solid.

EXAMPLE 3 ##STR37##

To a suspension of 2-hydroxybenzimidazole (0.134 g, 1.0 mmole) in dryDMF is added NaH, (45 mg, 1.1 mmole) at room temperature. The resultinghomogeneous solution is stirred for 10 minutes at room temperature andthen 2-chlorobenzoxazole (0.12 mL, 1.0 mmole) is added at a moderaterate via syringe. After stirring at room temperature for 1 h, water isadded to the reaction vessel and the resulting solid is collected viasuction filtration and washed successively with water, methanol andether to afford 3-(2-benzoxazyl)-benzimidazol-2-(1H)-one; (Compound 9);mp 245°-246° C. as a pale white solid.

EXAMPLE 4 ##STR38##

To a solution of (0.3 g, 1.9 mmole) of 4-fluoro-2-nitroaniline and (2.62g, 0.019 mole) of K₂ CO₃ in dry DMF is added (0.23 mL, 2.09 mmole) of2-chlorobenzoxazole at a moderate rate via syringe. After stirring atroom temperature for 12 h. water is added to the reaction vessel and theresulting solid is collected via suction filtration and washed withwater. The solid is then taken up in EtOAc, dried over anhydrous MgSO₄,filtered and solvent removed under reduced pressure. The resulting4fluoro-2-nitro-(2-benzoxazyl)-1-aniline is treated at 40 psi with H₂over 10% Pd/C in EtOH for 1 hr. The resulting mixture is filteredthrough Celite, washed with EtOH, and solvent removed under reducedpressure.

The resulting diamine is treated with 1,1'-Carbonyldiimidazole (CDI) atroom temperature in dry DMF for 12 hr. Water is added, the resultingsolid is collected via suction filtration and washed successively withwater, methanol and ether to afford3-(2-(benzoxazyl))-5-fluorobenzimidazol-2-(1H)-one; (Compound 10); mp287°-288° C., as a pale yellow solid.

EXAMPLE 5

The following compounds are prepared essentially according to theprocedures described in Examples 1-4, and as shown in Schemes 1-4:

(1) 3-(2-(5-fluorobenzoxazyl))-benzimidazol-2-(1H)-one; (Compound 11);mp: 400° C.

(2) 3-(2-(6-fluorobenzoxazyl))-benzimidazol-2-(1H)-one; (Compound 12);mp: 266°-268° C.

(3) 3-(2-(7-fluorobenzoxazyl))-benzimidazol-2-(1H)-one; (Compound 13);mp: 340°-345° C.

(4) 3-(2-(benzoxazyl))-6-fluorobenzimidazol-2-(1H)-one; (Compound 14);mp: 295°-296° C.

(5) 3-(2-(6-fluorobenzoxazyl))-6-fluorobenzimidazol-2-(1H )-one;(Compound: 4); mp 284°-285° C.

(6) 3-(2-(5-methoxybenzoxazyl))-benzimidazol-2-(1H)-one; (Compound 15);mp: 360°-362° C.

(7) 3-(2-(6-methoxybenzoxazyl))-benzimidazol-2-(1H)-one; (Compound 16);mp: 365°-367° C.

(8) 3-(2-(6,7-difluorobenzoxazyl))-benzimidazol-2-(1H)-one; (Compound17); mp: 360°-362° C.

(9) 3-(2-(7-fluorobenzoxazyl))-6-fluorobenzimidazol-2-(1H)-one;(Compound 3); mp: 284°-285° C.

(10) 3-(2-(7-fluorobenzoxazyl))-5-fluorobenzimidazol-2-(1H)-one;(Compound 18); mp: 268-270° C.

(11) 3-(2-(benzthiazyl))-benzimidazol-2-(1H)-one; (Compound 19); mp:291°-293° C.

(12) 3-(2-benzoxazyl)-4,5,6,7-tetrahydrobenzimidazol-2-(1H)-one;(Compound 20); mp: 205°-205° C.

(13)3-(2-(6-fluorobenzoxazyl)-,4,5,6,7-tetrahydrobenzimidazol-2-(1H)-one;(Compound 21); mp: 255°-258° C.

(14)3-(2-(5-fluorobenzoxazyl)-1,4,5,6,7-tetrahydrobenzimidazol-2-(1H)-one;(Compound 22).

(15)3-(2-(5-methoxybenzoxazyl)-,4,5,6,7-tetrahydrobenzimidazol-2-(1H)-one;(Compound 6); mp: 214°-217° C.

(16)3-(2-(6,7-difluorobenzoxazyl)-,4,5,6,7-tetrahydrobenzimidazol-2-(1H)-one:(Compound 5); mp: 228°-231° C.

(17)3-(2-(6-methoxybenzoxazyl)-,4,5,6,7-tetrahydrobenzimidazol-2-(1H)-one;(Compound 23); mp: 211°-214° C.

(18) 3-(2-benzoxazyl)-1,4,5,6,7,8-hexahydrocycloheptylimidazol-2-one;(Compound 24); mp: 164°-166° C.

(19)3-(2-(6-fluorobenzoxazyl)-1,4,5,6,7,8-hexahydrocycloheptylimidazol-2-one;(Compound 2); mp: 190°-192° C.

(20)3-(2-(5-fluorobenzoxazyl)-1,4,5,6,7,8-hexahydrocycloheptylimidazol-2-one;(Compound 25); mp: 206°-209° C.

(21)3-(2-(7-fluorobenzoxazyl)-1,4,5,6,7,8-hexahydrocycloheptylimidazol-2-one;(Compound 26); mp: 208°-210° C.

(22)3-(2-(5-methoxybenzoxazyl)-1,4,5,6,7,8-hexahydrocycloheptylimidazol-2-one;(Compound 27); mp: 225°-227° C.

(23)3-(2-(6,7-difluorobenzoxazyl)-1,4,5,6,7,8-hexahydrocycloheptylimidazol-2-one;(Compound 1); mp: 204°-206° C.

(24)3-(2-(6-methoxybenzoxazyl)-1,4,5,6,7,8-hexahydrocycloheptylimidazol-2-one;(Compound 28); mp: 211°-213° C.

(25) 3-(2-(6-methylbenzoxazyl))-benzimidazol-2-(1H)-one; (Compound 29);mp: 350° C. (dec.).

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula: ##STR39## or thepharmaceutically acceptable non-toxic salts thereof wherein R_(p),R_(q), and R_(s) are independently hydrogen, fluoro, methoxy, or methyl,with the proviso that at least one of said R_(p), R_(q), and R_(s) ishydrogen.